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3D Printing of hydrogel composite systems: Recent advances in technology for tissue engineering

The in situ incorporation of particles into hydrogel In the case of long and continuous fiber-reinforced
scaffolds during and/or after 3D printing is more-effective hydrogel systems, research has shown substantially
approach than the ex situ method for achieving uniform improved mechanical performances due to the
distribution and high loadings, because post-loaded particles continuous fiber-hydrogel matrix interactions as opposed
do not hinder the printing process (Figure 5B). Jeong et al. to disconnected interactions in short-fiber-reinforced
proposed a great potential of in situ precipitation process hydrogels. As such, the load transmittance from the
for high- and uniform-loading capacity with minimal matrix to each fiber also becomes more continuous.
agglomeration into a polymer matrix . Precipitated calcium However, in spite of its outstanding performance, the most
phosphate (CaP) nanoparticles with 200–350 nm were challenging issue for applying this composite system to
easily formed and incorporated from calcium chloride and the 3D printing process are practical ways to achieve an
phosphoric acid mixed solutions. Compared with same uniform distribution and intended alignment of continuous
concentration of pre-mixed CaP nanoparticles, precipitated fibers within the hydrogel matrix. Narayanan et al. tried
HAc-CaP composite hydrogels exhibited homogeneous to fabricate alginate-nanofiber bioink for 3D-bioprinting
distribution and approximately five times higher storage which could provide protection for encapsulated cells
[93]
moduli values. In addition, mechanical properties were during the digitally driven fabrication process . To prepare
continuously increased by increasing concentration of the composite hydrogel, pre-fabricated portions of PLA
[15]
precipitated CaP up to 40 wt% . Very recently, Egorov nanofiber was mixed with alginate (ratio 1:5, w/w), and
et al. combined in situ mineralization with 3D printing agitated in a vortex mixer, and finally sonicated for 2 hours.
in which calcium chloride and ammonium hydrogen Despite all these efforts, continuous PLA nanofibers were
phosphate solutions were mixed with sodium alginate slurry aggregated and poorly distributed within hydrogel matrix,
and then 3D-bioplotter printing was employed to fabricate which is mainly attributed to the strong van der Waal’s
a cubic-shaped 3D composite structure (8 × 8 × 5 mm). attraction between the sub-micron scaled aggregated fibers
The compressive strength of composite hydrogels were (Figure 7B). In this paper, they could not prove there were
gradually increased from 0.4 to 1.0 MPa with increasing any mechanical enhancement of nanofiber-reinforced
concentration of precipitated CaP up to 2.0 wt%. However, composite hydrogels, but the nanofiber-reinforced bioink
overall mechanical properties of 3D printed scaffold showed better cell proliferation and metabolic activity
were relatively low due to the weak bonding between levels of human adipose-derived stem cells (hASC) within
filaments, which is a major limitation of the in situ particle printed 3D structure that were encapsulated with cells [93] .
[99]
incorporation approach for composite hydrogel systems . Agrawal et al. approached this issue from a different
3.3 Fiber-reinforced Hydrogel Composites 3D angle. To build continuous fiber-PEG composite scaffold,
Printing elastic polyurethane (PU) fibers are printed first to form a
“log-pile” structure, and then fabricated continuous fibers
Fiber reinforcements can also improve mechanical properties were impregnated with the PEG gel. The PU polymer
of hydrogel matrix in which the fiber contents and its solution was placed into a pressure-driven syringe fitted
distribution inside its matrix determine mechanical properties with a 100 µm needle, and mounted on the dispensing 3D
such as stiffness and strength of composites [92–95] . In the case printing system. The entire printing process was performed
of common 3D printing systems, short fiber reinforcements under water to form a continuous elastic micro fiber rapidly
are the most commonly used due to its easy processing though solvent exchange. As with 24 wt% continuous
procedure at low cost. The fibers can be directly incorporated fibers, the elastic modulus of composites were two-
into the hydrogel matrix via simple mixing and transferred times higher, and the maximum strain-to-break ratio was
into the syringe for printing. Gladman et al. proposed stiff greatly improved compared to that of pure hydrogels .
[94]
cellulose fibrils as a short fiber reinforcement and printed Bakarich et al. developed a more advanced technique for
cellulose-acrylamide composite hydrogel 3D structures. For fiber-reinforced hydrogel composite system using a one-
[95]
ensuring smooth, clog-free print behavior of composite ink, step process . The previous approach requires at least a
the maximum concentration of nanofibrillated cellulose inside two-step fabrication process involving the 3D printing of
a soft acrylamide matrix should not exceed 0.8 wt%, which continuous fiber scaffold structure followed by immersion
was then transferred into the 3D-bioplotter cartridge and of the scaffold into a hydrogel precursor solution, and
injected through stainless steel commercial nozzles of varying crosslinking. However, recent development of UV curable
diameters. During the printing process, short fibers inside the material and light system of 3D printing have made it
composite ink undergo shearing forces due to the small nozzle possible to fabricate fiber reinforced hydrogel composites
size and orientate themselves along the printing direction, using a one-step 3D-bioplotter process. This composite
as shown in Figure 7A. This in turn induces anisotropic was printed by selectively patterning a combination of two
mechanical properties of printed filaments such as anisotropic different UV curable inks: one is alginate/acrylamide gel
[92]
stiffness and swelling behaviors . solution for the matrix, and the other is adhesive epoxy

14 International Journal of Bioprinting (2018)–Volume 4, Issue 1